Lineage Plasticity, due to Disruption of MnSOD Biology, drives resistance to Ionizing Radiation / Androgen Deprivation Therapy

总结--这一新的R01应用的首要目标是研究线粒体的失调 负责维持正常新陈代谢的网络是癌症的既定标志。这种扰乱 细胞代谢，导致活性氧物种(ROS)的异常积累，引发 不适应信号是导致电离辐射(IR)抵抗(IRR)的一种新兴的新机制 以及对苯扎鲁胺(ENZ)的抗性(ENZR)。在这方面，最近发现了一种线粒体信号 中轴线以锰超氧化物歧化酶(MnSOD)为中心，当乙酰化(Ac)时赖氨酸的状态 68(K68-Ac)被改变，扰乱细胞新陈代谢，导致ROS水平异常(朱，自然通讯， 2019年)。此外，表达MnSODK68-Ac模拟突变体(MnSODK68Q)的LNCaP细胞表现出IRR/ENZR， 增加了HIF2A和两个干细胞标记物Oct4和SOX2，HIF2A已知可以促进茎的特性。因此， 我们试图证明MnSOD-K68-Ac可能通过改变MnSOD的结构组成来驱动IRR和/或ENZR 和酶活性，在更广泛的背景下，肿瘤的生长和生存通过细胞干细胞样机制。 最后，GC4419暴露，一种模拟MnSOD的化学试剂，是否会逆转IRR/ENZR 表型？由此推测，暴露于IRR和/或ENZR的前列腺肿瘤细胞增加了MnSOD- K68-Ac，在细胞和线粒体水平上扰乱正常的MnSOD生物学(即异常的ROS)，这 通过增加HIF2A启动细胞重新编程，导致谱系可塑性特性，即肿瘤的变化 细胞命运，以及IRR和/或ENZR肿瘤表型。还提出了MnSOD-K68-Ac是一种新型的轴系。 IRR和IRR/ENZR肿瘤的新治疗措施。最后，使用GC4419，化学上 取代MnSOD活性，我们询问超氧化物歧化是否恢复/转换这些IRR/ENZR前列腺 通过恢复正常代谢使肿瘤细胞转变为敏感表型

SUMMARY - The overarching goal of this new R01 application is to investigate the dysregulation of mitochondrial networks responsible for maintaining normal metabolism is an established hallmark of cancer. This disruption of cellular metabolism, leads to the aberrant accumulation of reactive oxygen species (ROS), triggering maladaptive signaling that is an emerging, novel mechanism leading to ionizing radiation (IR) resistance (IRR) as well as enzalutamide (ENZ) resistance (ENZR). In this regard, recently identified a mitochondrial signaling axis centered on manganese superoxide dismutase (MnSOD) which, when the acetylation (Ac) status of lysine 68 (K68-Ac) is altered, disrupts cellular metabolism, leading to aberrant ROS levels (Zhu, Nature Commun., 2019). In addition, LNCaP cells expressing a MnSOD K68-Ac mimic mutant (MnSODK68Q) exhibited IRR/ENZR, increased HIF2a, known to promote stemness properties, and two stem cell markers, Oct4 and SOX2. As such, we seek to show that MnSOD-K68-Ac may drive IRR and/or ENZR, by altering MnSOD’s structural composition and enzymatic activity, and in a broader context, tumor growth and survival via a cell stemness-like mechanism. Finally, will GC4419 exposure, a chemical agent that acts as a MnSOD mimic, reverse the IRR/ENZR phenotype? Thus, it is hypothesized that prostate tumor cells exposed to IRR and/or ENZR increase MnSOD- K68-Ac, disrupting normal MnSOD biology at the cellular and mitochondrial level (i.e., aberrant ROS), which initiates cellular reprogramming, via increased HIF2a, leading to lineage plasticity properties, a change in tumor cell fate, and an IRR and/or ENZR tumor phenotype. It is also proposed that MnSOD-K68-Ac is a novel axis for new therapeutic interventions in IRR and IRR/ENZR tumors. Finally, using GC4419, which that chemically replaces MnSOD activity, we ask whether superoxide detoxification reverts/converts these IRR/ENZR prostate tumor cells to a sensitive phenotype by restoring normal metabolism